[5]Helicenes by iterative radical cyclisations to arenes

Article abstract of DOI:10.1016/S0040-4039(02)00506-3

The paper describes a synthesis of 1,2,3,12,13,14-hexamethoxy[5]helicene 1. The synthesis features two sp²-sp² bond forming reactions, each involving a 6-exo/endo-trig cyclisation of an aryl radical intermediate to an arene.

Full text of DOI:10.1016/S0040-4039(02)00506-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3189–3191
[5]Helicenes by iterative radical cyclisations to arenes
David C. Harrowven,a,* Michael I. T. Nunna and David R. Fenwickb
aDepartment of Chemistry, The University of Southampton, Southampton SO17 1BJ, UK
bDiscovery Chemistry, Pfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
Received 12 February 2002; accepted 7 March 2002
Abstract—The paper describes a synthesis of 1,2,3,12,13,14-hexamethoxy[5]helicene 1. The synthesis features two sp2–sp2 bond
forming reactions, each involving a 6-exo/endo-trig cyclisation of an aryl radical intermediate to an arene. © 2002 Elsevier Science
Ltd. All rights reserved.
Intramolecular radical additions to arenes have
acquired greater prominence in recent years as their
value in synthesis has become more widely appreci-
ated.1,2 Our main contribution has been to show that
6-exo/endo-trig radical cyclisations to pyridines, quino-
lines and arenes are often facile and high yielding
processes.3–5 One extension of the method we were keen
to explore involved its application in an iterative sense
for the preparation of [5]helicenes (Scheme 1). Herein
we report our realisation of that objective through a
short synthesis of 1,2,3,12,13,14-hexamethoxy[5]-
helicene 1.
the desired cis-stilbene 14 (48% yield), and again
column chromatography readily effected its separation
from trans-14 (19%). To complete the synthesis of
[5]helicene 1, cis-stilbene 14 was exposed to tributyltin
hydride under standard radical forming conditions.5
This gave 1,2,3,12,13,14-hexamethoxy[5]helicene 1 and
1,2,3,8,9,10-hexamethoxydibenzo[a,h]anthracene 15 in
52% and 17% yields, respectively (Scheme 2).
The clear preference for cyclisation of radical interme-
diate 2 to C-5 of the phenanthrene moiety rather than
C-7 is notable (Scheme 3). Though the origin of that
selectivity has yet to be established with rigor, we
presume it reflects a more favourable SOMO–LUMO
interaction with C-5. The formation of 1 as the major
product additionally suggests that cyclisation to 16 or
17 and the subsequent loss of a hydrogen atom are
irreversible: the lack of products derived from migra-
tion of the alkene tether lending further support to this
hypothesis.
The synthesis began with the union of 5 and 7 using a
standard Wittig olefination procedure. Pleasingly this
gave rise to an easily separable 13:2 mixture of cis- and
trans-stilbenes 8 in 97% yield. Treatment of cis-8 with
tributyltin hydride under standard radical forming con-
ditions then provided phenanthrene 9 in 85% yield.5 A
series of functional group interconversions next trans-
formed the nitrile function into a phosphonium salt,
facilitating the preparation of stilbene 14 by a Wittig
olefination with 5. This too proved to be selective for
In conclusion, we have developed a new approach to
[5]helicenes in which two sp2–sp2 coupling reactions are
OMe
OMe
OMe
OMe
OMe
OMe
MeO
OMe
OMe
OMe
MeO
OMe
OMe
OMe
OMe
CN
1
2
3
Scheme 1.
Keywords: helicenes; radicals and radical reactions; cyclisation; polycyclic aromatic compounds.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00506-3

3190
D. C. Harrow6en et al. / Tetrahedron Letters 43 (2002) 3189–3191
MeO
MeO
CHO
MeO
MeO
CHO
I
MeO
MeO
a
I
OMe
OMe
OMe
OMe
d
OMe
OMe
4
5
c
P+Ph3 Br–
b
Br
CN
CN
NC
NC
8
9
6
7
OMe
OMe
OMe
OMe
OMe
MeO
OMe
OMe
OMe
OMe
OMe
OMe
e
i
j
+
MeO
OMe
OMe
MeO
MeO
MeO
MeO
X
10 X = CHO
f
I
11 X = CH2OH
g
h
MeO
14
MeO
15
12 X = CH2Br
13 X = CH2P+Ph3 Br–
1
Scheme 2. Reagents and conditions: a. I2, AgCO2CF3, DCM, 7 h, rt, 92%;6 b. PPh3, PhMe, reflux, 6 h, 96%;7 c. NaH, THF,
0°C“rt, 2 h; add 5 at 0°C“rt, 2 h, 97% (Z:E–13:2); d. Bu3SnH, AIBN, PhMe, 90°C, 36 h; KF(aq), rt, 16 h, 85%;5 e. DIBAL-H,
PhMe, 0°C, 1 h, 81%;8 f. NaBH4, THF, rt, 4 h, 96%; g. PBr3, PhH, rt, 2 h, 85%; h. PPh3, PhMe, reflux, 6 h, 70%; i. NaH, THF,
0°C“rt, 2 h; add 5 at 0°C“rt, 16 h, 67% (Z:E–5:2); j. Bu3SnH, AIBN, PhMe, 90°C, 16 h; KF(aq), rt, 16 h, 69% (1:15–3:1).5
14
Bu3Sn•
–Bu3SnI
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
minor
major
H
MeO
OMe
MeO
MeO
MeO
OMe
OMe
MeO
OMe
16
2
17
-'H•' 17%
-'H•' 52%
15
1
Scheme 3.
accomplished by 6-exo/endo-trig cyclisation of an aryl
radical to an arene.5 The synthesis demonstrates the
potential of this method in the construction of strained
polyaromatics and has led to a greater understanding of
the mechanistic course of this recently uncovered
reaction.
References
1. For recent examples of radical additions to arenes see: (a)
Clive, D. L. J.; Kang, S. J. Org. Chem. 2001, 66, 6083; (b)
Leardini, R.; McNab, H.; Minozzi, M.; Nanni, D. J.
Chem. Soc., Perkin Trans. 1 2001, 1072; (c) Harrowven, D.
C.; Nunn, M. I. T.; Newman, N. A.; Fenwick, D. R.
Tetrahedron Lett. 2001, 42, 961; (d) Ishibashi, H.;
Kobayashi, T.; Nakashima, S.; Tamura, O. J. Org. Chem.
2000, 65, 9022; (e) Senboku, H.; Hasegawa, H.; Orito, K.;
Tokuda, M. Tetrahedron Lett. 2000, 41, 5699; (f) Amrein,
S.; Bossart, M.; Vasella, T.; Studer, A. J. Org. Chem. 2000,
65, 4281; (g) Bowman, W. R.; Mann, E.; Parr, J. J. Chem.
Soc., Perkin Trans. 1 2000, 2991; (h) Wakabayashi, K.;
Acknowledgements
The authors thank Pfizer Global Research and Devel-
opment and the EPSRC for their financial support
through an Industrial CASE award (to M.I.T.N.).

D. C. Harrow6en et al. / Tetrahedron Letters 43 (2002) 3189–3191
3191
Yorimitsu, H.; Shinokubo, H.; Oshima, K. Org. Lett.
2000, 2, 1899; (i) Clive, D. L. J.; Kang, S. Tetrahedron
Lett. 2000, 41, 1315; (j) Studer, A.; Bossart, M.; Vasella, T.
Org. Lett. 2000, 2, 985; (k) Ishibashi, H.; Ohata, K.;
Niihara, M.; Sato, T.; Ikeda, M. J. Chem. Soc., Perkin
Trans. 1 2000, 547; (l) Bonfand, E.; Forslund, L.; Mother-
well, W. B.; Va´zquez, S. Synlett 2000, 475; (m) Mother-
well, W. B.; Va´zquez, S. Tetrahedron Lett. 2000, 41, 9667;
(n) Wang, S.-F.; Chuang, C.-P.; Lee, J. H.; Liu, S.-T.
Tetrahedron 1999, 55, 2273; (o) Ishibashi, H.; Toyao, A.;
Takeda, Y. Synlett 1999, 1468; (p) Ishibashi, H.;
Kobayashi, T.; Takamasu, D. Synlett, 1999, 1286; (q)
Studer, A.; Bossart, M.; Steen, H. Tetrahedron Lett. 1998,
39, 8829; (r) Aicaide, B.; Rodr´ıguez-Vincente, A. Tetra-
hedron Lett. 1998, 39, 6589; (s) Studer, A.; Bossart, M.
Chem. Commun. 1998, 2127; (t) Amii, H.; Kondo, S.;
Uneyama, K. Chem. Commun. 1998, 1845; (u) Godfrey, C.
R. A.; Hegarty, P.; Motherwell, W. B.; Uddin, M. K.
Tetrahedron Lett. 1998, 39, 723; (v) Giraud, L.; Lacoˆte, E.;
Renaud, P. Helv. Chim. Acta 1997, 80, 2148; (w) Rosa, A.
M.; Lobo, A. M.; Branco, P. S.; Prabhakar, S. Tetra-
hedron 1997, 53, 285; (x) Bonfand, E.; Motherwell, W. B.;
Pennell, A. M. K.; Uddin, M. K.; Ujjainwalla, F. Hetero-
cycles 1997, 46, 523; (y) da Mata, M. L. E. N.; Mother-
well, W. B.; Ujjainwalla, F. Tetrahedron Lett. 1997, 38,
141; (z) da Mata, M. L. E. N.; Motherwell, W. B.;
Ujjainwalla, F. Tetrahedron Lett. 1997, 38, 137.
2. For a recent overview see: Studer, A.; Bossart, M. Tetra-
hedron 2001, 57, 9649.
3. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetra-
hedron Lett. 2001, 42, 9061; (b) Harrowven, D. C.; Nunn,
M. I. T.; Blumire, N. J.; Fenwick, D. R. Tetrahedron 2001,
57, 4447; (c) Harrowven, D. C.; Nunn, M. I. T.; Blumire,
N. J.; Fenwick, D. R. Tetrahedron Lett. 2000, 41, 6681; (d)
Harrowven, D. C.; Nunn, M. I. T. Tetrahedron Lett. 1998,
39, 5875.
4. (a) Harrowven, D. C.; Sutton, B. J.; Coulton, S. Tetra-
hedron 2002, 58, in press; (b) Harrowven, D. C.; Sutton, B.
J.; Coulton, S. Tetrahedron Lett. 2001, 42, 2907.
5. (a) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R.
Tetrahedron Lett. 2002, 43, 3185; (b) Aidhen, I. S.;
Narasimhan, N. S. Indian J. Chem. Sect. B 1993, 32, 211.
6. Bradley, A.; Motherwell, W. B.; Ujjainwalla, F. Chem.
Commun. 1999, 10, 917.
7. Rafizadeh, K.; Yates, K. J. Org. Chem. 1984, 49, 1500.
8. Wen, L.; Li, M.; Schlenoff, J. B. J. Am. Chem. Soc. 1997,
119, 7726.